What is urticaria and how is it treated?

Urticaria, sometimes called nettle fever, nettle rash, is a skin disease, dermatitis of mainly allergic origin, characterized by the rapid onset of itchy, flatly raised pale pink blisters similar in appearance to blisters from a nettle burn.

According to the modern definition, urticaria is a group of diseases distinguished by the occurrence of itchy blisters and/or angioedema, i.e. swelling.

Conditions in which blisters are a symptom do not apply to urticaria. Among them: skin tests, auto-inflammatory syndromes (diseases induced by mutations in protein-coding genes that play a leading role in the regulation of the inflammatory response), anaphylaxis.

Clinical forms of urticaria

The disease can be acute and chronic. Characteristic features of acute spontaneous urticaria: occurrence of blisters and/or swelling within fewer than six weeks. Chronic urticaria is diagnosed when the symptoms are present for more than six weeks. In some cases, the only symptom is angioedema.

Chronic urticaria is split into spontaneous and induced. The reason for the occurrence of spontaneous chronic urticaria is unknown external factors, while the induced urticaria develops when exposed to certain external physical stimuli (cold, heat, vibration, pressure, etc.).

One patient may have two or more different forms of urticaria.

Classification of chronic urticaria

Slow urticaria from pressure is edema at the site of pressure, which develops within a few hours after exposure to an inducing factor. In individuals with chronic urticaria, the development of isolated edema without blisters is possible.

Previously, the following diseases and syndromes that included urticaria or allergic swelling as one of the symptoms were also assigned to urticaria:

- Pigmentary urticaria (mastocytosis);
- Urticarial vasculitis;
- Family cold urticaria;
- Nonhistaminergic angioedema (for example, hereditary angioedema);
- Exercise-induced allergic reaction;
- Cryopyrine-associated syndromes (ATS):
- Family cold auto-inflammatory syndrome;
- Muckle-Wells syndrome;
- Neonatal multisystemic inflammatory diseases;
- Schnitzler Syndrome - monoclonal gammopathy, recurrent fever, arthritis, pain in muscles and bones, lymphadenopathy, hepatosplenomegaly, recurrent urticaria;
- Gleich's syndrome (episodic swelling) - IgM gammopathy, eosinophilia, myalgia, angioedema.

Currently, these diseases are treated separately and do not apply to urticaria.

Incidence of urticaria

Urticaria is a very common disease. Its various clinical variants are diagnosed in 15–25% of people in the world. Approximately one in three people has experienced hives during their lives at least once. A quarter of all cases are chronic. Adults get sick more frequently than kids.

Chronic spontaneous urticaria accounts for 60% of chronic disease cases. Usually, it starts to manifest at the age between 20 and 40 years. Females are affected by this disease 2 times more often than men, possibly, due to the peculiarities of the neuroendocrine system.

In adults, the disease is present on average from 3 to 5 years, and every fifth patient has blisters over a longer period (up to 20 years). Characteristic swelling is observed in every second patient.

Mechanism of urticaria development

The leading mechanism for the onset of urticaria is the reactin damage mechanism. As an allergen, medicines (antibiotics, X-ray contrast agents, etc.), serums, gamma globulins, bacterial polysaccharides, food products, and insect allergens are more often. The second type of damage mechanisms may be triggered by a blood transfusion. The immune complex mechanism can be activated with the introduction of a number of medicines, antitoxic sera, and gamma globulin.

Pseudo-allergic urticaria is a result of the effect of histamine liberals, complement activators, or the kallikrein-kinin system (medications, physical factors, food products containing xenobiotics).

There is also a theory that the main role in chronic urticaria plays the incorrect reaction of the immunity to the organism’s own cells, i.e. autoimmune response. This theory is based on the fact that in the majority of patients autoantibodies of IgG and IgE classes are found.

Diagnosis of urticaria

The diagnosis is based on the patient’s complaints, physical examination, and survey aimed at finding other manifestations of allergy, for instance, nasal discharges, sneezing, itching of the eyes or nose, etc.

Besides, the diagnosis also requires the identification of an allergen to eliminate or avoid it for the easier curing of disease. This is done by the skin prick test that implies the insertion of microdoses of allergens and the analysis of the body reaction.

Assessment of urticaria severity

To assess the intensity of the symptoms in chronic urticaria, the simple score scale named Urticaria Activity Score 7 is used. It implies the total assessment of the main symptoms of the disease by the patients themselves every 24 hours for 7 consecutive days. Each symptom is rated in points from 0 to 3. Total points per day - from 0 to 6, per week (maximum amount - 42 points).

Treatment of urticaria

The focus of the disease treatment is taking under control itching and blisters formation.

The therapy always begins with the elimination of the causes and triggers if possible; suspected medicines, for instance, angiotensin-converting enzyme inhibitors, NSAIDs are excluded. It is recommended to avoid stresses and conditions of overheating or hypothermia (especially in severe inducible urticaria).

Also, a diet that excludes causally significant allergens and histaminolibrators is prescribed. The diet is both a diagnostic and a therapeutic measure. When eliminating the identified allergens from the diet, improvement occurs within 24−48 hours. In the case of a pseudo-allergic reaction, an improvement with a hypoallergenic diet occurs after 3 weeks.

In general, therapy of urticaria with medications is symptomatic.

If Quincke's edema (severe allergic swelling) develops, emergency treatment with intravenous administration of epinephrine, prednisolone, and oxygen inhalation is required. In mild and moderate cases, when life-threatening swelling does not occur, other symptomatic medicines are used:

- Antihistamines blocking H1 receptors and suppress immediate allergic reactions are the basis of therapy. First-generation antihistamines block both central and peripheral H1 receptors, so they can be very sedative, i.e. cause sleepiness. Second-generation antihistamines, such as levocetirizine (Alerzin), Fexofenadine, and others, selectively block only peripheral H1 receptors. They cause fewer side effects and do not cause sleepiness. To get the maximum therapeutic effect, it is crucial to take antihistamines constantly, and not only in case of exacerbations. If an individual doesn’t respond to the highest dosages of H1 antihistamines may receive H2 antihistamines. However, not all combinations are useful.  The best effect have the combinations of hydroxyzine with cimetidine, but not cetirizine and cimetidine.
- Monoclonal anti-IgE antibodies. Omalizumab was approved by the FDA for chronic idiopathic urticaria in individuals older than 12 years. It is used as an alternative treatment when antihistamines are ineffective.
-  Oral glucocorticoids are effective for chronic urticaria. However, they have a high likelihood and a big number of negative effects such as suppression of adrenal gland function, weight gain, osteoporosis,  and others.  Their use should be limited to several weeks. There is no point to combine them with antihistamines as the effectiveness will not rise.
- Leukotriene receptor antagonists.  Medicines such as montelukast and zafirlukast act on another side of the allergic process, they block leukotriene receptors and can be used as an addition to the main treatment or as an alternative. This group of medicines is especially effective in individuals with NSAIDs-induced urticaria.

Other medicines for urticaria

Other treatment options for complex cases of chronic urticaria include anti-inflammatory medicines, omalizumab, and immunosuppressants.

- Anti-inflammatory medicines: dapsone, sulfasalazine, and others. Dapson suppresses the development of herpetiform dermatitis, presumably due to the ability to inhibit enzymes or exhibit oxidizing properties, or as a result of an immunotropic (immunosuppressive) effect.
Sulfasalazine, a derivative of 5-aminosalicylic acid, is thought to affect adenosine release and inhibit mast cell degranulation mediated by immunoglobulin E.
- Hydroxychloroquine is an antimalarial drug that suppresses T-lymphocytes. It is cheap but requires longer treatment than dapsone or sulfasalazine.
- Immunosuppressants use is left for severe cases only due to their potentially serious adverse reactions. The immunosuppressants used to treat urticaria include cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil.
- Calcineurin inhibitors, such as cyclosporin and tacrolimus, inhibit mast cell response, and inhibit T-cell activity. Some experts recommend them for the therapy of persistent forms of urticaria. To date, cyclosporin is the only medicine introduced into the modern algorithm for disease treatment. It should be considered in the case of omalizumab failure. The therapy with the medication requires frequent monitoring of liver, kidney, and blood tension. Long-term therapy, i.e. more than three months, is not recommended.

Post by: Rachel Lewis, Senior Medical Advisor at Medibank, Sydney, New South Wales, Australia